Biotechnology in the 21st century presents the possibility of new solutions to the food, environment, and health problems, with the ultimate goal of improving human welfare. In recent years, the therapy using stem cells has been considered as a new way to treat incurable diseases. Formerly, organ transplantation, gene therapy, etc., were presented for the treatment of incurable human diseases, but their efficient use has not been made due to immune rejection, short supply of organs, insufficient development of vectors, and insufficient knowledge of disease genes.
As an alternative to solve these problems, the interest in stem cells has grown, and it has been recognized that totipotent stem cells having the ability to form all organs by proliferation and differentiation can be applied to the treatment of most diseases as well as to the treatment of incurable diseases, including Parkinson's disease, various cancers, diabetes, spinal cord injuries, etc.
Stem cells refer to cells having not only self-replication ability but also the ability to differentiate into at least two cells, and embryonic stem cells, induced pluripotent stem cells, and adult stem cells have been most actively studied. Among others, in the case of embryonic stem cells and induced pluripotent stem cells, there are still limitations in their application to the human body due to ethical issues or stability issues such as tumorigenesis. The adult stem cells are advantageous in terms of stability, and thus clinical studies have been conducted in patients. However, among the adult stem cells, in the case of neural stem cells and cord blood cells, the autograft, which is the transplantation of their own cells, is not yet feasible, and thus it is necessary to transplant neural stem cells from other people. Bone marrow or fat-derived mesenchymal stem cells can be easily obtained from the human body and thus have been most actively studied in clinical trials.
With respect to cell therapy using mesenchymal stem cells, a long-term clinical research on cell therapy for isolation and proliferation of mesenchymal stem cells from their own bone marrow, followed by intravenous transplantation, has been reported (Bang O Y, Lee J S, Lee P H, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005; 57:874-882) (Lee J S, Hong J M, Moon G J, Lee P H, Ahn Y H, Bang O Y. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010; 28:1099-1106). However, even in the case of mesenchymal stem cells with these advantages, it takes more than 4 to 5 weeks to culture mesenchymal stem cells isolated from bone marrow to reach a sufficient concentration (about 1×108 cells) that can be used for cell therapy, which is problematic.
As such, the autograft is impossible depending on the types of stem cells, or even when autograft is feasible, it takes a long time to culture stem cells until a desired therapeutic effect is achieved, and thus research on allograft has been conducted. That is, the use of cells derived from a healthy person is much easier than the use of cells derived from a patient, and thus extensive research on cell therapy using allogeneic stem cells has recently been actively conducted.
However, even in the development of allogeneic therapies with the above-described advantages, the following problems have been reported:
(a) It has been reported that stem cells derived from a healthy person and stem cells from a patient (e.g., a stroke patient) have different characteristics. That is, it has been reported that stem cells derived from bone marrow of a stroke animal are excellent in functional recovery after stroke, compared to stem cells derived from bone marrow of a healthy animal (Zacharek A, Shehadah A, Chen J, Cui X, Roberts C, Lu M, Chopp M. Comparison of bone marrow stromal cells derived from stroke and normal rats for stroke treatment. Stroke. 2010; 41:524-530). Therefore, even during the allograft, it is necessary to activate stem cells to be suitable for transplantation by applying appropriate stimuli to stem cells, instead of simply transplanting stem cells from other people. Moreover, even in the case of stem cells derived from a patient, the characteristics of stem cells are likely to vary during culture in fetal bovine serum for a long time;
(b) After a predetermined time from transplantation of stem cells, the number of stem cells is significantly reduced, and this results from cell death that occurs when stem cells are in a toxic environment such as cerebral infarction and myocardial infarction. Therefore, in the stem cell therapy, it is important to improve the viability of stem cells to be transplanted such that stem cells can survive in this environment for a long time to maintain the therapeutic effect;
(c) The effect of cell therapy after the occurrence of acute injuries such as cerebral infarction and myocardial infarction is determined by how fast stem cells are transplanted. However, as mentioned above, even in the transplantation of autologous or allogeneic stem cells, it takes a long time to culture stem cells to a concentration suitable for cell therapy, which makes it impossible to transplant stem cells to a patient in need of treatment in a timely manner. Therefore, it is necessary to reduce the culture period by increasing the proliferation rate by applying appropriate stimuli to stem cells to be activated and further minimize the loss of conditioning that have been applied to stem cells at the time of acute injury during culture; and
(d) Fetal bovine serum (FBS) is generally used for the culture of stem cells, but it has been reported that some fetal bovine serum is introduced into stem cells, causing the risk of zoonoses such as bovine spongiform encephalopathy.
As such, various limitations have been reported with the use of autologous or allogeneic stem cells in the stem cell therapy to treat brain injured patients, but a suitable method for inducing the activation of stem cells to overcome these limitations has not yet been reported. Therefore, in order to overcome the existing limitations of stem cell therapy, it is necessary to develop a method for activating stem cells to be suitable for stem cell therapy.